Reactions with β-cyanoethylhydrazine—I : A route for the preparation of pyrazolo[1.5-a]pyrimidines and pyrrolo[1.2-b]pyrrazoles

Malononitrile (1) reacts with β-cyanoethylhydrazine (2) to yield 5-amino-4-cyano-1-β-cyanoethyl-3-cyanomethyl-pyrazole (3). Treatment of 3 with 1% NaOH solution results in the formation of 3-cyano-2-cyanomethyl-4,5,6,7-tetrahydropyrazolo[1.5-a] pyrimine (6). On the other hand, when 3 was refluxed with acetic acid-hydrochloric acid mixture, the pyrido[3:4:3′:4′]pyrazolo[1.5-a] pyrimidine (10) was formed.1,2-Dihydro-5-hydroxy-3-phenylazopyrazolo[1.5-a] pyrimidine (16) was obtained by cyclization of 3,5-dianimo-1-(β-cyanoethyl)-4-phenylazopyrazole (18), which, in turn, was obtained by the action of 2 on phenylazomalononitrile (17).Ethoxymethylenemalononitrile (20) reacts with 2 to yield 3-amino-4-cyano-1-β-cyanoethyl)-pyrazole (21). Compound 21 was readily cyclized into the pyrrolo[1.2-b]pyrazole derivative 25 by the action of either 3% NaOH solution or conc sulphuric acid.     

A study of 1,5-hydrogen shift and cyclization reactions of an alkali isomerized methyl linolenoate

Heating a mixture formed by alkali isomerization of methyl linolenoate (1) produces a complex mixture with the bicyclic hexahydroindenoic esters 4β-(7-methoxycarbonylheptyl)-5α-methyl-2,3,3aα,4,5,7aαhexahydroindene (CL5) and 4β-ethyl-5α-(6-methoxycarbonylhexyl)-2,3,3aα,4,5,7aα-hexahydroindene (CL6) as main components. Similar isomerization reactions of three synthetic model compounds, methyl 9Z,13E,15Z-octadecatrienoate (2), 9Z,14E,16E-octadecatrienoate (4) and 9Z,11E,15Z-octadecatrienoate (5) corroborated the results obtained with alkali isomerized methyl linolenoate.     

Total synthesis of the sesquiterpene (±)-hirsutene using an organoselenium-mediated cyclization reaction

Cyclization of 2-carbomethoxy-3-(4',4'-dimethylcyclopent-2-enylmethyl)cyclopentanone (4) with N-phenylselenophthalimide and tin(IV) chloride affords cis-syn-cis-1β-carbomethoxy-4,4-dimethyl-3β-phenylselenotricyclo [6.3.0.0^2,6]undecan-11-one (8) and cis-anti-cis-1β-carbomethoxy-4,4-dimethyl-3α-phenylselenotricyclo [6.3.0.0^2,6]undecan-11-one (9). Both of these selenides can be elaborated to cis-anti-cis-4,4-dimethyl-1β-methyltricyclo [6.3.0.0^2,6]undecan-11-one (13) which upon treatment with CH₂Br₂/ TiCl₄/Zn affords the sesquiterpene (±)-hirsutene (1) in 20% overall yield.     

Synthesis of 1-(β-cyanoethyl)-4-ethynyl-2, 5-dimethyl-4-piperidinols and the corresponding 4-vinyl compounds

Synthesis of 1-(β-cyanoethyl)-4e-ethynyl-2e, 5e-dimethylpiperidin-4a-o1 and the corresponding 4e-vinyl compounds (β-isomers), 1-β-cyanoethyl-4a-ethynyl-2e, 5e-dimethylpiperidin-4c-ol (and the corresponding 4a-vinyl compound) (γ-isomers), and l-(β-cyanoethyl)-2e, 5a-dimethyl-4a-vinylpiperidin-4e-o1 (α-isomer) have been effected.     

Four new norlignan glycoside isomers from the twigs of Cephalotaxus oliveri Mast.

Four novel isomers of norlignan glycoside were isolated from Cephalotaxus oliveri Mast.. Their structures were elucidated as 3S-4″-O-β-d-glucopyranosylnyasol 1, 3S-4′-O-β-d-glucopyranosylnyasol 2, 3S-4″-O-β-d-glucopyranosylhinokiresinol 3, 3S-4′-O-β-d-glucopyranosylhinokiresinol 4 by extensive spectroscopic methods including 1D and 2D NMR experiments (¹H, ¹³C, DEPT, ¹H–¹H COSY, HSQC, HMBC, ROESY) along with HR-ESIMS and comparison to literature data. Their absolute configurations were elucidated through CD spectra coupled with the quantum chemical CD calculations.     

Synthesis of 1-(3′-deoxy-β-D-glycero-pentofuran-2′-ulosyl)uracil by selective elimination reactions

For the synthesis of y 1-(3′-deoxy-β-D-glycero-pentofuran-2′-ulosyl)uracil (16), the precursor, 5′-O-benzoyl derivative (2),² was elaborated in a variety of ways. 1-(5′-O-Benzoyl-3′-O-tosyl-β-D- lyxofuranosyl)uracil (4)² was benzoylated to N³-benzoyl-1-(2′,5′-di-O-benzoyl-3′-O-tosyl-β-D- lyxofuranosyl)uracil (5), which directly yielded 2 on treatment with sodium benzoate. 1-(3′,5′-Di-O- benzoyl-2′-O-tosyl-β-D-lyxofuranosyl)uracil (8) and its 3′,5′-O-isopropylidene analog (10) resisted elimination reactions, thus proving absolute selectivity in the elimination of the derivatives of 1-β-D- lyxofuranosyl-uracil. Seeking a more economical path to 2, 1-(5′-O-benzoyl-β-D-lyxofuranosyl)uracil (11) was first benzoylated to give 2′,5′-di-O-benzoate (12), accompanied by 3′,5′-di- and 2′,3′,5′-tri-O- benzoate. Mesylation of the major product (12) gave 1-(2′,5′-di-O-benzoyl-3′-O-mesyl-β-D- lyxofuranosyl)uracil (15), which, on treatment with sodium benzoate, gave 2 in an highly improved yield. Basic hydrolysis on 2 gave compound 16.     

Synthesis of enantiomerically pure spiro-cyclopropane derivatives containing multichiral centers

A novel chiral source, 5-(R)-[(1R,2S,5R)-(−)-menthyloxy]-3-bromo-2(5H)-furanone (5a), was obtained in 46% yield with d.e.≥98% from the epimeric mixture of 5-(l-menthyloxy)-3-bromo-2(5H)-furanone (5a+5b) obtained via the bromination of an epimeric mixture of 5-(l-menthyloxy)-2(5H)-furanone (3a+3b) followed by the elimination of hydrogen bromide. The asymmetric reaction of 5a with a nucleophilic alcohol afforded enantiomerically pure spiro-cyclopropane derivatives containing four stereogenic centers, 9a–9e, in 50–68% yield with d.e.≥98%. The enantiomerically pure compounds 9a–9e were identified on the basis of their analytical data and spectroscopic data, such as [α]_D²⁰, UV, IR, ¹H NMR, ¹³C NMR, MS and elementary analysis. The absolute configuration of the chiral spiro-cyclopropane compound 9a was established by X-ray crystallography.     

Synthesis and antifungal activities of novel trifluoroethane derivatives with coumarin,indole and thiophene

A series of novel 1-(β-coumarinyl)-1-(β-indolyl)-1-(α-thiophenyl)trifluoroethane derivatives 5aaa-5hdb were prepared by one-pot reaction from 3-(trifluoroacetyl)coumarin with indole and α-substituted thiophene. Their structures were confirmed by ¹H NMR, ¹³C NMR, ¹⁹F NMR, HRMS and X-ray single crystal diffraction, and their antifungal activities against F. moniliforme, F. graminearum, F. oxysporum, R. solani and P. nicotianae were evaluated. The title compounds displayed significant to moderate in vitro antifungal activity when compared to the standard drug triadimefon. Among the synthesized compounds, compound 5bfa showed the highest inhibitor rate of 83.5 % at 0.500 mg/mL against R. solani, while compound 5ada displayed the highest inhibitor rate of 73.3 % at 0.500 mg/mL against F. graminearum.     

Photochemistry of β,γ-enones-VIII: On the remarkable photostability of some β,γ.β',γ'-dienones and the 1,3-acyl shift photoreactivity of two β,γ.γ',δ'-dienones

The direct irradiation of the β,γ.β',γ'-dienones 1–5 and the β,γ.γ',δ'-dienones (E)-6a, (E)-7a and 8a at λ 300 nm has been studied. The β,γ.β,γ'-dienones 1–5 are remarkable photostable for λ ? 300 nm, even upon prolonged irradiation, in contrast to simple β,γ-enones which upon irradiation exhibit α-cleavage, γ-hydrogen abstraction, (E)-(Z) isomerization and oxetane formation. The observed photostability of the β,γ.β',γ'-dienones is rationalized in terms of a rapid radiationless decay of the excited singlet state, enhanced by CT-interaction between the carbonyl ¹(n-π*) state and the homoconjugated 1,4-diene moiety, which precludes fluorescence, photochemical reactions and intersystem crossing (ISC).The β,γ.γ',δ'-dienones (E)-(6a), (E)-7a and 8a exhibit only a 1,3-acyl shift (1,3-AS) without (E)-(Z) isomerization of the alkenyl moiety, to yield (E)-6b, (E)-7b and 8b. It is concluded that the 1,3-AS proceeds from the ¹(n-π*) state with a rate which is very large relative to the rate of ISC to the ³(n-π*) state, thus precluding any internal triplet energy transfer (1TET) from the ³(n-π*) to the ³(π-π*) state which would manifest itself by (E)-(Z) isomerization.     

Lipase-mediated partial resolution of 1,2-diol and 2-alkanol derivatives: towards chiral building-blocks for pheromone synthesis

1,2-Propanediol 5, 1-chloro-2-propanol 8 and its related 2-O-acetate 9 were partially resolved by chemoenzymatic acetylation and deacetylation, in the presence of Pseudomonas fluorescens lipase (Amano P.; PFL), to (R)-(−)-1-acetoxy-2-propanol 6, (R)-(+)-2-acetoxy-1-chloropropane 9 and (R)-(−)-1-chloro-2-propanol 8, respectively. On the other hand, treatment of (2RS)-2 with vinyl acetate in ether and Chirazyme^® L-2 gave 2-O-acetyl-1,3,4-trideoxy-5,6:7,8-di-O-isopropylidene-β-d-manno-non-5-ulo-5,9-pyranose 1 and 1,3,4-trideoxy-5,6:7,8-di-O-isopropylidene-β-d-gluco-non-5-ulo-5,9-pyranose 11, respectively. Compound 10 was subsequently deacylated to 12. Both alcohols 11 and 12 were treated with Me₂CO/H⁺ to cause their rearrangement to (2S,5R,8R,9R,10S)-10-hydroxy-8,9-isopropylidenedioxy-2-methyl-1,6-dioxaspiro[4.5]decane 3 and its (2R)-epimer 4, which closely matched the skeleton of the odour bouquet minor components of Paravespula vulgaris (L.).     

Preparation of both enantiomers of β-(3,4-dihydroxybenzyl)-β-alanine, higher homologues of Dopa

β²-(3,4-Dihydroxybenzyl)-β-alanine [β²-Homo-Dopa, 1] is a novel β-amino acid homologue of Dopa, the most successful therapeutic agent in the treatment of Parkinson's disease. Enantioenriched (R)-1 and (S)-1 were obtained via the diastereoselective alkylation of enantiopure pyrimidinone (R)- and (S)-3, chiral derivatives of β-alanine, with veratryl iodide. The major diastereomeric products (2S,5R)-4 and (2R,5S)-4 were hydrolyzed with 57% HBr, and the desired β-amino acids were purified by silica gel chromatography. Alternatively, enantioenriched (R)- and (S)-1 were prepared by means of the highly diastereoselective alkylation (3,4-dimethoxybenzyl iodide) of open-chain β-aminopropionic acid derivatives (R,R,S)-8 and (S,S,R)-8 containing the chiral auxiliary α-phenylethylamine. Finally, nearly enantiopure (R)- and (S)-1 were obtained by resolution of racemic N-benzyloxycarbonyl-2-(3,4-dibenzyloxybenzyl)-3-aminopropionic acid, rac-12, with (R)- or (S)-α-phenylethylamine, followed by catalytic hydrogenolysis.     

One-dimensional coordination polymers generated from an oxadiazole-containing N,N′-bipyridine-type ligand and Cu(II) salts

Three new Cu(II) coordination polymers have been prepared using Cu(II) salts in combination with 2,5-bis(4-pyridyl)-1,3,4-oxadiazole (L2). The compounds were characterized by single crystal X-ray diffraction, IR spectroscopy, and elemental analysis. In the solid state, all three new polymeric compounds 1–3 (1: monoclinic, P2/c, a=10.0956(11) Å, b=6.8710(7) Å, c=18.6152(19) Å, β=97.270(2)°, V=1280.9(2) ų, Z=2; 2: monoclinic, P2₁/c, a=9.2275(5) Å, b=16.0479(9) Å, c=18.3403(3) Å, β=91.1260(10)°, V=2715.4(3) ų, Z=4; 3: triclinic, P-1, a=6.9932(7) Å, b=11.5777(12) Å, c=12.5291(13) Å, α=109.401(2)°, β=103.922(2)°, γ=95.316(2)°, V=912.06 ų, Z=2) feature novel one-dimensional single or double-sinusoidal chain motifs with different repeat periods, which result from the different conformations adopted by the L2 ligand.     

A new route for the preparation of the 22,23-dioxocholestane side chain from diosgenin and its application to the stereocontrolled construction of the 22R,23S-diol function

The new (22R,23S,25R)-3β,16β,26-triacetoxy-cholest-5-ene-22,23-diol (11a) was synthesized from diosgenin (3) through a synthetic route based on chemoselective RuO₄ oxidation of (25R)-3β,16β-diacetoxy-23-ethyl-23¹,26-epoxycholesta-5,23(23¹)-dien-22-one (9) that afforded (20S,25R)-3β,16β,26-triacetoxycholest-5-ene-22,23-dione (10) which was stereoselectively reduced using NaBH₄. Compound 9 was obtained from the known isomeric 22,26-epoxycholest-5-ene steroidal skeleton 8b by treatment with p-TsOH in toluene, amberlyst-15 or directly from diosgenin by treatment with BF₃·OEt₂/Ac₂O. Chemoselective reduction of the 23-keto group of 10, was attained using NaBH₄/ZnCl₂ at −70 °C to give 23S-14. The NMR spectra of all compounds were unambiguously assigned based on one and two dimensional experiments and the C-22 and C-23 stereochemistry in the diacetate derivative 11b, as well as the structure of epoxycholestene 9 were further established by X-ray diffraction analyses. The new route for the functionalization of the side chain of diosgenin can find application in the synthesis of norbrassinosteroid analogues.     

Structures of the tricyclododecenes prepared by the catalytical intramolecular cyclisation of 1,5,9-cyclododecatriene

The internal cyclisation of 1,5,9-cyclododecatriene, induced by a catalytical amount of Cp₂TiCl₂-LAHδ, leads to a mixture of cis, anti, cis-tricyclo[7.3.0.0^2,6]-7-dodecene (1), cis,syn,trans-tricyclo[7.3.0.0^2,6]-7-dodecene (2), trans,syn-tricyelop[7.3.0.0^2,6]-6-dodecene (3) and 5,6,7,8,9,10-hexahydrobenzocyclooctene (4). The structures of the main products were determined from the spectra of a number of derivatives taking into account symmetry properties and configurational flexibility.     

One-dimensional coordination polymers generated from an oxadiazole-containing N,N′-bipyridine-type ligand and inorganic salts

Three new one-dimensional coordination polymers have been prepared using Hg(II), Ag(I) and Zn(II) inorganic salts in combination with 2,5-bis(3-pyridyl)-1,3,4-oxadiazole (L6). The compounds were characterized by single crystal X-ray diffraction, IR spectroscopy, and elemental analysis. In the solid state, compounds 1 and 3 (1: monoclinic, P2₁/n, a=5.5373(3) Å, b=16.7839(9) Å, c=16.8120(9) Å, β=92.8610(10)°, V=1560.52(15) ų, Z=4; 3: monoclinic, P2₁/n, a=7.2958(4) Å, b=11.7214(6) Å, c=16.3979(9) Å, β=101.1150(10)°, V=1375.99(13) Å³, Z=4) feature novel one-dimensional helical chain motif. Compound 2, however, (2: monoclinic, P2₁/c, a=5.5506(4) Å, b=16.5895(12) Å, c=16.6871(11) Å, β=95.424(2)°, V=1529.70(19) ų, Z=4) exhibits one-dimensional zigzag chain motif, which result from the different conformations adopted by the L6 ligand and also the different metal coordination geometry. The luminescent properties of three new compounds were investigated in the solid state.     

An enantiomerically pure bilirubin. Absolute configuration of (αR,α′R)-dimethylmesobilirubin-XIIIα

Enantiomerically pure (+)-(αR,α′R)-dimethylmesobilirubin-XIIIα 1 and its (αS,α′S) enantiomer ent-1 were synthesized in ten steps from simple precursors. Resolution was achieved at an early stage in the synthesis, with a racemic monopyrrole precursor rac-6 being converted to its amides 8 with (1S)-camphor-2,10-sultam. Resolution of 8 to 99% d.e. was accomplished in three crystallizations, and the absolute configuration of the acid 6 was deduced by X-ray crystallography of the more crystalline, diastereomerically pure amide 7. Circular dichroism spectroscopy of 1 showed intense bisignate Cotton effects: Δε^max₄₃₅=+344, Δε^max₃₉₁=−193 (CHCl₃), as expected for a molecular exciton, and consistent with a P-helical intramolecularly hydrogen-bonded ridge-tile conformation. The Cotton effect magnitudes of 1 match almost exactly those found for (−)-(βS,β′S)-dimethylmesobilirubin-XIIIα 11 and (+)-(αR,β′R)-dimethylmesobilirubin-XIIIα. However, the Cotton effect of the pseudo-meso diastereomer (αR,β′S)-dimethylmesobilirubin-XIIIα 12 is not zero. Its large positive exciton couplet and ¹H NMR NOE analysis confirm that an α-CH₃ exerts a greater steric demand than a β-CH₃—by a factor of ∼3.     

Synthesis of chiral 1- and 2-(p-tolylsulfinyl)-3-trimethylsilyloxybuta-1,3-dienes and their behaviour in Diels–Alder cycloadditions

The synthesis of (±)-(E)-1-(p-tolylsulfinyl)-3-trimethylsilyloxybuta-1,3-diene 1 and (S_S)-2-(p-tolylsulfinyl)-3-trimethylsilyloxybuta-1,3-diene 2 and their reactions with cyclic dienophiles are described. Cycloaddition of diene 1 with N-methylmaleimide 10 was performed under pressure affording a complex reaction mixture from which two epimers at C-3′, (±)-11a and (±)-11b [2,3,3a,4,5,7a-hexahydro-2-methyl-7a-(1-methylsuccinimide-3-yl)-1H-isoindole-1,3,5-triones], were isolated in equal amounts. Diene (±)-1 cycloadded to the more reactive 4-methyl-1,2,4-triazoline-3,5-dione 14 at atmospheric pressure and room temperature. However, nothing can be said about the stereochemical outcome of this addition since the loss of the chiral auxiliary via the sulfoxide–sulfenate rearrangement gave the bicyclic α,β-unsaturated ketone 17 (2-methyl-2,3,5,6-tetrahydro-1H-[1,2,4]triazolo[1,2-a]pyridazine-1,3,6-trione). Diels–Alder cycloaddition of enantiopure diene 2 with 10 occurred under pressure leading to a diastereomeric mixture of adducts where the trimethylsilyl enol ether moiety spontaneously evolved to the ketone function. The major enantiopure product 18a [(3aS,6S,7aR,R_S)-2-methyl-6-(p-tolylsulfinyl)perhydroisoindole-1,3,5-trione] was isolated and characterized. Cycloadditions of both dienes to dienophile 10 appear highly stereoselective.     

Synthesis of large chelate rings with diphosphites built on a cyclodextrin scaffold. Unexpected formation of 1,2-phenylene-capped α-cyclodextrins

Two primary face difunctionalised α-cyclodextrins (α-CDs) bearing AC and AD-positioned triarylphosphite ligands have been synthesised and their ability to form large chelate rings has been evaluated. 6^A,6^D-Bis-O-{2-〚(diphenoxyphosphino)oxy〛phenyl}-2^A,2^B,2^C,2^D,2^E,2^F,3^A,3^B,3^C,3^D,3^E,3^F,6^B,6^C,6^E,6^F-hexadeca-O-methyl-α-cyclodextrin (L1) was prepared in three steps in 59% overall yield: (i) treatment of 6^A,6^D-di-O-(methylsulfonyl)-2^A,2^B,2^C,2^D,2^E,2^F,3^A,3^B,3^C,3^D,3^E,3^F,6^B,6^C,6^E,6^F-hexadeca-O-methyl-α-cyclodextrin (1a) with sodium 2-(benzyloxy)phenolate, affording a mixture of the corresponding bisaryloxy substitution product 2a; (ii) cleavage of the benzyl groups of 2a with formation of bisphenol 6a; (iii) reaction of 2a with chlorodiphenylphosphite to afford L1. Diphosphite L2 was obtained in a similar manner using the AC dimesylate 1b (yield: 54%). In step (i) of each synthesis, the unexpected formation of a catecholato-capped CD was observed as a result of benzyl loss under the used arylation conditions. The AD-bridged product was characterised by a single crystal X-ray diffraction study. In the solid state, the CD torus adopts the usual circular shape while four glucose rings, although not distorted, are considerably tilted towards the cavity axis. Both ligands, L1 and L2, when reacted with the cationic complexes AgBF₄ or 〚Rh(norbornadiene)(THF)₂〛X (X = BF₄, PF₆), produced selectively chelate complexes having up to 29-membered metallomacrocycles in high yields. Rhodium systems based on either L1 or L2 catalyse effectively the hyfroformylation of 1-octene (TOF up to 1200 mol mol^–1 of Rh h^–1). Hydrogenation of dimethyl itaconate with a Rh(I)/L2 complex produced dimethyl (R)-(+)-methylsuccinate with an EE as high as 83.6%.     

Three New Myrsinol Diterpenes from <em>Euphorbia prolifera</em> and Their Neuroprotective Activities

Three new myrsinol diterpenes were isolated from the roots of Euphorbia prolifera. Their structures were elucidated as 2α-O-isobutyryl-3β,5α,7β,10,15β-penta-O-acetyl-14α-O-benzoyl-10,18-dihydromyrsinol (1), 2α-O-isobutyryl-3β-O-propion-yl-5α,7β,10,15β-tetra-O-acetyl-10,18-dihydromyrsinol (2), and 2α,14α-di-O-benzoyl-3β,5α,7β,10,15β-penta-O-acetyl-10,18-dihydromyrsinol (3) on the basis of spectroscopic data analyses (IR, ESI-MS, HR-ESI-MS, and 1D and 2D NMR). Their neuroprotective activities were evaluated and compounds 1 and 2 showed neuroprotective effects against MPP⁺-induced neuronal cell death in SH-SY5Y cells.     

The dynamic kinetic resolution of 3-oxo-4-phenyl-β-lactam by recombinant E. coli overexpressing yeast reductase Ara1p

Using a recombinant E. coli strain overexpressing yeast reductase Ara1p, we reduced racemic 3-oxo-4-phenyl-β-lactam to cis-(3S,4R)-3-hydroxy-4-phenyl-β-lactam as a single enantiopure product. The dynamic kinetic resolution occurred over the course of fermentation at pH 7. Under the same conditions, 3-oxo-4-(2-thiophenyl)-β-lactam 4 and 3-oxo-4-(2-furyl)-β-lactam 5 were not resolved.